Mitochondrial genome copy number measured by DNA sequencing in human blood is strongly associated with metabolic traits via cell-type composition differences

Liron Ganel,Lei Chen,Allison Regier,Erica Young,Chul Joo Kang,Jagadish Vangipurapu,Krishna L Kanchi ,Nathan O Stitziel,Alexandra J Scott ,Indraniel Das,Michael Boehnke,Ryan Christ,Haley Abel ,Samuli Ripatti,Aki S Havulinna ,Adam E Locke ,Nelson B Freimer ,Aarno Palotie,David E Larson ,Johanna Kuusisto,Charleston W K Chiang,Markku Laakso,Ira M Hall

doi:10.1186/s40246-021-00335-2

Abstract

BackgroundMitochondrial genome copy number (MT-CN) varies among humans and across tissues and is highly heritable, but its causes and consequences are not well understood. When measured by bulk DNA sequencing in blood, MT-CN may reflect a combination of the number of mitochondria per cell and cell-type composition. Here, we studied MT-CN variation in blood-derived DNA from 19184 Finnish individuals using a combination of genome (N = 4163) and exome sequencing (N = 19034) data as well as imputed genotypes (N = 17718).ResultsWe identified two loci significantly associated with MT-CN variation: a common variant at the MYB-HBS1L locus (P = 1.6 × 10−8), which has previously been associated with numerous hematological parameters; and a burden of rare variants in the TMBIM1 gene (P = 3.0 × 10−8), which has been reported to protect against non-alcoholic fatty liver disease. We also found that MT-CN is strongly associated with insulin levels (P = 2.0 × 10−21) and other metabolic syndrome (metS)-related traits. Using a Mendelian randomization framework, we show evidence that MT-CN measured in blood is causally related to insulin levels. We then applied an MT-CN polygenic risk score (PRS) derived from Finnish data to the UK Biobank, where the association between the PRS and metS traits was replicated. Adjusting for cell counts largely eliminated these signals, suggesting that MT-CN affects metS via cell-type composition.ConclusionThese results suggest that measurements of MT-CN in blood-derived DNA partially reflect differences in cell-type composition and that these differences are causally linked to insulin and related traits.

Highlights

Mitochondrial genome copy number (MT-CN) varies among humans and across tissues and is highly heritable, but its causes and consequences are not well understood
MT-CN was strongly associated with fat mass (P = 4.48 x 10-16) and fasting serum insulin (P = 2.02 x 10-21), as well as numerous additional quantitative traits, many related to metabolic syndrome (Fig. 1a, Table S1 - Additional File 2)
As further evidence that MT-CN is a proxy for blood cell composition, we looked up MT-CN association P values in METSIM for the top five neutrophil and platelet count quantitative trait loci (QTL) from the NHGRI-EBI Genome-wide association studies (GWAS) Catalog [51]

Summary

Introduction

Mitochondrial genome copy number (MT-CN) varies among humans and across tissues and is highly heritable, but its causes and consequences are not well understood. Traits associated with mitochondrial (MT) content include CHD, type 2 diabetes, and metabolic syndrome traits such as insulin sensitivity/resistance, obesity, and blood triglycerides. These studies have generally been limited by small sample sizes and low statistical power. In one large WGS study of mitochondrial genome copy number (MT-CN) in 2077 Sardinians, Ding et al estimated the heritability of MT-CN at 54% and detected significant associations between MT-CN and both waist circumference and waist–hip ratio, but found no association with body mass index (BMI) [15] Another large study (N = 5150) found virtually no evidence of association between qPCR-measured MT-CN and any of several cardiometabolic phenotypes [23]. A study of 21870 individuals from 3 cohorts showed a significant inverse relationship between MTCN (measured by microarray probe intensities in two cohorts and qPCR in the third) and incident cardiovascular disease [24]

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